Prognostic Impact of the Administration of Antibiotics and Proton Pump Inhibitors in Immune Checkpoint Inhibitor Combination Therapy for Advanced Renal Cell Carcinoma.

Background/Aim: The prognostic impact of the administration of antibiotics and proton pump inhibitors (PPIs) in immune checkpoint inhibitor (ICI) therapy for advanced cancer has recently been documented. However, how these drugs affect the outcomes of first-line ICI combination therapy for advanced renal cell carcinoma (RCC) remains unclear. Patients and Methods: We retrospectively evaluated the data of 128 patients with RCC who received first-line ICI combination therapy. The patients were grouped according to their history of antibiotics and PPIs use one month before the initiation of ICI combination therapy. Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) after ICI combination therapy were compared between patients treated with and without antibiotics or PPIs. Results: Of the 128 patients, 30 (23%) and 44 (34%) received antibiotics and PPIs, respectively. Patients treated with antibiotics exhibited shorter PFS and OS compared to those who did not receive antibiotics (median PFS: 4.9 vs. 16.1 months, p<0.0001; OS: 20.8 vs. 49.0 months, p=0.0034). Multivariate analyses showed that antibiotic administration was an independent predictor of shorter PFS (hazard ratio: 2.54: p=0.0002) and OS (hazard ratio: 2.56: p=0.0067) after adjusting for other covariates. In contrast, there were no significant differences in either PFS or OS between patients who received PPIs and those who did not. (PFS: p=0.828; OS: p=0.105). Conclusion: Antibiotics administration before ICI combination therapy was negatively associated with outcomes of first-line ICI combination therapy for advanced RCC. Therefore, careful monitoring is required for potentially high-risk patients undergoing ICI combination therapy.

Unveiling Spatial Immune Cell Profile in Kidney Allograft Rejections Using 36-plex Immunofluorescence Imaging.

BACKGROUND: Kidney allograft rejections are orchestrated by a variety of immune cells. Because of the complex histopathologic features, accurate pathological diagnosis poses challenges even for expert pathologists. The objective of this study was to unveil novel spatial indices associated with transplant rejection by using a spatial bioinformatic approach using 36-plex immunofluorescence image data. METHODS: The image obtained from 11 T cell-mediated rejection (TCMR) and 12 antibody-mediated rejection (AMR) samples were segmented into 753 737 single cells using DeepCell's Mesmer algorithm. These cells were categorized into 13 distinct cell types through unsupervised clustering based on their biomarker expression profiles. Cell neighborhood analysis allowed us to stratify kidney tissue into 8 distinct neighborhood components consisting of unique cell type enrichment profiles. RESULTS: In contrast to TCMR samples, AMR samples exhibited a higher frequency of neighborhood components that were characterized by an enrichment of CD31+ endothelial cells. Although the overall frequency of CD68+ macrophages in AMR samples was not significantly high, CD68+ macrophages within endothelial cell-rich lesions exhibited a significantly higher frequency in AMR samples than TCMR samples. Furthermore, the frequency of interactions between CD31+ cells and CD68+ cells was significantly increased in AMR samples, implying the pivotal role of macrophages in AMR pathogenesis. Importantly, patients demonstrating a high frequency of CD31:CD68 interactions experienced significantly poorer outcomes in terms of chronic AMR progression. CONCLUSIONS: Collectively, these data indicate the potential of spatial bioinformatic as a valuable tool for aiding in pathological diagnosis and for uncovering new insights into the mechanisms underlying transplant rejection.

Robot-assisted Partial Nephrectomy With Selective Artery Clamping for Renal Cell Carcinoma in Horseshoe Kidney.

BACKGROUND: Robot-assisted partial nephrectomy (RAPN) has become the standard treatment for small renal tumors, including highly complex cases. However, applying RAPN to renal tumors in the horseshoe kidney (HSK) is clinically challenging due to malformations and complex blood supply. Herein, we present two cases of RAPN in patients with HSK treated using selective artery clamping methods. CASE REPORTS: A 61-year-old male with a 15 mm renal tumor located on the upper pole of the right HSK was referred to our Department. The patient underwent RAPN via the transperitoneal approach, following a three-dimensional computed tomography (3D-CT) assessment. Additionally, before surgery, we confirmed which renal arteries would be clamped in surgery by examining the kidney regions supplied by each renal artery. The second patient referred to our Department, a 45-year-old male, had a 46 mm renal tumor located on the isthmus of the HSK. His tumor received blood supply from two renal arteries, with the bilateral collecting systems converging and forming a ureter on 3D-CT. The patient underwent RAPN through an intraperitoneal approach in the semi-lateral position, with port placement lower than in standard RAPN. Pathological examinations revealed clear-cell renal cell carcinoma with negative surgical margins in both cases. Both patients had no recurrences or metastases at 53 and 13 months post-surgery, respectively. CONCLUSION: We present cases successfully treated with RAPN with selective artery clamping methods for HSK using 3D-CT without encountering complications, even in isthmus tumors.

Survival Impact of Glucocorticoid Administration for Adverse Events During Immune Checkpoint Inhibitor Combination Therapy in Patients with Previously Untreated Advanced Renal Cell Carcinoma.

BACKGROUND: The impact of glucocorticoid administration for adverse events (AEs), including immune-related AEs, on the effectiveness of immune checkpoint inhibitor (ICI) combination therapy for advanced renal cell carcinoma (RCC) remains unknown. OBJECTIVES: To clarify the prognostic impact of glucocorticoid use for AEs during first-line ICI combination therapy for advanced RCC. PATIENTS AND METHODS: We retrospectively evaluated data from 194 patients who received dual ICI combination therapy [i.e., immunotherapy (IO)-IO] or combinations of ICIs with tyrosine kinase inhibitors (TKIs) as first-line therapy. The patients were divided into two groups according to the history of glucocorticoid administration in each treatment group. Survival based on glucocorticoid administration was assessed. RESULTS: A total of 101 (52.0%) and 93 (48.0%) patients received IO-IO and IO-TKI combination therapy, respectively. Glucocorticoids were administered to 46 (46%) and 22 (24%) patients in the IO-IO and IO-TKI groups, respectively. In the IO-IO group, progression-free survival (PFS) and overall survival (OS) were significantly longer in patients with glucocorticoid administration than in those without administration (median PFS: 14.4 versus 3.45 months, p = 0.0005; median OS: 77.6 versus 33.9 months, p = 0.0025). Multivariable analysis showed that glucocorticoid administration was an independent predictor of longer PFS (hazard ratio: 0.43, p = 0.0005) and OS (hazard ratio: 0.35, p = 0.0067) after adjustment for covariates. In the IO-TKI group, neither PFS nor OS significantly differed between patients treated with and without glucocorticoid administration (PFS: p = 0.0872, OS: p = 0.216). CONCLUSIONS: Glucocorticoid administration did not negatively impact the effectiveness of ICI combination therapy for RCC, prompting glucocorticoid treatment use when AEs develop.

Impact of body composition on outcomes of immune checkpoint inhibitor combination therapy in patients with previously untreated advanced renal cell carcinoma.

BACKGROUND: Data on the association between body composition and outcomes in patients with advanced renal cell carcinoma (RCC) treated with immune checkpoint inhibitor (ICI) combination therapy are limited. METHODS: We retrospectively evaluated the clinical and radiographic data of 159 patients with advanced RCC, including 84 receiving ICI dual combination therapy (immunotherapy [IO]-IO group) and 75 receiving combinations of ICIs with tyrosine kinase inhibitors (TKIs) (IO-TKI group). Pretreatment computed tomography images were used to calculate body composition, including skeletal muscle mass and fat tissue area. Sarcopenia was defined based on skeletal muscle and psoas muscle indexes. The total fat index, subcutaneous fat index (SFI), and visceral fat index were also calculated. RESULTS: In the IO-IO treatment group, there was no significant association between body composition and survival or tumor response (P > 0.05). In the IO-TKI treatment group, the high SFI was associated with longer progression-free survival (hazard ratio, 2.70; P = 0.0091) and overall survival (hazard ratio, 26.0; P = 0.0246) than the low SFI, which remained significant after adjusting for covariates. Furthermore, in the high-SFI population, patients treated with IO-TKI therapy had longer progression-free survival (P = 0.0019) and overall survival (P = 0.0287) than those treated with IO-IO therapy, while there was no significant survival difference between the 2 treatment groups in the low-SFI population (P > 0.05). CONCLUSION: The SFI can be potentially utilized as an effective predictive and prognostic biomarker for first-line ICI combination therapy for advanced RCC.

Molecular subtypes of lung adenocarcinoma present distinct immune tumor microenvironments.

Overcoming resistance to immune checkpoint inhibitors is an important issue in patients with non-small-cell lung cancer (NSCLC). Transcriptome analysis shows that adenocarcinoma can be divided into three molecular subtypes: terminal respiratory unit (TRU), proximal proliferative (PP), and proximal inflammatory (PI), and squamous cell carcinoma (LUSQ) into four. However, the immunological characteristics of these subtypes are not fully understood. In this study, we investigated the immune landscape of NSCLC tissues in molecular subtypes using a multi-omics dataset, including tumor-infiltrating leukocytes (TILs) analyzed using flow cytometry, RNA sequences, whole exome sequences, metabolomic analysis, and clinicopathologic findings. In the PI subtype, the number of TILs increased and the immune response in the tumor microenvironment (TME) was activated, as indicated by high levels of tertiary lymphoid structures, and high cytotoxic marker levels. Patient prognosis was worse in the PP subtype than in other adenocarcinoma subtypes. Glucose transporter 1 (GLUT1) expression levels were upregulated and lactate accumulated in the TME of the PP subtype. This could lead to the formation of an immunosuppressive TME, including the inactivation of antigen-presenting cells. The TRU subtype had low biological malignancy and "cold" tumor-immune phenotypes. Squamous cell carcinoma (LUSQ) did not show distinct immunological characteristics in its respective subtypes. Elucidation of the immune characteristics of molecular subtypes could lead to the development of personalized immune therapy for lung cancer. Immune checkpoint inhibitors could be an effective treatment for the PI subtype. Glycolysis is a potential target for converting an immunosuppressive TME into an antitumorigenic TME in the PP subtype.

Advanced Renal Cell Carcinoma With Inferior Vena Cava Thrombus Treated With a Combination of Preoperative Lenvatinib and Pembrolizumab.

BACKGROUND/AIM: Lenvatinib plus pembrolizumab combination therapy is a safe and effective treatment for patients with advanced renal cell carcinoma (RCC). However, there are no reports of the use of lenvatinib and pembrolizumab combination therapy for RCC with an inferior vena cava (IVC) tumor thrombus. Herein, we describe a case in which pembrolizumab and lenvatinib combination therapy was effectively used to treat RCC with the IVC tumor thrombus extending to the right atrium. CASE REPORT: A 73-year-old man was diagnosed with a right renal tumor with the IVC tumor thrombus extending to the right atrium and multiple pulmonary metastases (cT3cN0M1). Using a computed tomography-guided renal tumor biopsy, the tumor was diagnosed as clear cell RCC. The International Metastatic RCC Database Consortium risk classification was poor according to three risk factors, and lenvatinib and pembrolizumab combination therapy was initiated. The primary renal tumor shrunk, the IVC tumor thrombus that reached the right atrium was reduced from level 4 to level 2, and the lung metastases disappeared 4 months after treatment initiation. Thereafter, a robot-assisted deferred cytoreductive nephrectomy was successfully performed. Pathologically, owing to the preoperative combination therapy, most of the tumor tissue was necrotic; however, some viable cells were present in the primary tumor and IVC tumor thrombus. Eight months following the operation, the patient remains recurrence-free. CONCLUSION: Treatment with lenvatinib and pembrolizumab combination therapy led to tumor shrinkage and allowed robot-assisted nephrectomy in a patient with advanced RCC with the IVC tumor thrombus extending to the right atrium, corroborating the efficacy of the treatment.

Automated angular measurement for puncture angle using a computer-aided method in ultrasound-guided peripheral insertion.

Ultrasound guidance has become the gold standard for obtaining vascular access. Angle information, which indicates the entry angle of the needle into the vein, is required to ensure puncture success. Although various image processing-based methods, such as deep learning, have recently been applied to improve needle visibility, these methods have limitations, in that the puncture angle to the target organ is not measured. We aim to detect the target vessel and puncture needle and to derive the puncture angle by combining deep learning and conventional image processing methods such as the Hough transform. Median cubital vein US images were obtained from 20 healthy volunteers, and images of simulated blood vessels and needles were obtained during the puncture of a simulated blood vessel in four phantoms. The U-Net architecture was used to segment images of blood vessels and needles, and various image processing methods were employed to automatically measure angles. The experimental results indicated that the mean dice coefficients of median cubital veins, simulated blood vessels, and needles were 0.826, 0.931, and 0.773, respectively. The quantitative results of angular measurement showed good agreement between the expert and automatic measurements of the puncture angle with 0.847 correlations. Our findings indicate that the proposed method achieves extremely high segmentation accuracy and automated angular measurements. The proposed method reduces the variability and time required in manual angle measurements and presents the possibility where the operator can concentrate on delicate techniques related to the direction of the needle.

First-line dual immune checkpoint inhibitor therapies versus combination therapies comprising immune checkpoint inhibitors and tyrosine kinase inhibitors for advanced renal cell carcinoma: a comparative analysis of the effectiveness using real-world data.

BACKGROUND: There are few comparative studies on dual immune checkpoint inhibitors (ICIs) (i.e., IO-IO) and combination therapies comprising ICIs plus tyrosine kinase inhibitors (TKIs) (i.e., IO-TKI) for advanced renal cell carcinoma (RCC), especially in real-world settings. METHODS: We retrospectively evaluated data of 175 patients with IMDC intermediate-risk or poor-risk RCC; as first-line therapy, 103 received IO-IO, and 72 received IO-TKI. An inverse probability of treatment weighting (IPTW) analysis was conducted to balance patients' backgrounds in the IO-IO and IO-TKI groups. RESULTS: Based on the IPTW analysis, progression-free survival (PFS) was longer in the IO-TKI group than in the IO-IO group (median: 15.6 vs. 8.3 months; p = 0.0386). In contrast, overall survival was not different between groups (median: 46.7 vs. 49.0 months; p = 0.465). Although the IPTW-adjusted objective response rate was not significantly different (51.2% vs. 43.9%; p = 0.359), the progressive disease rate as the best overall response was lower in the IO-TKI group than in the IO-IO group (3.3% vs. 27.4%; p < 0.0001). Regarding the safety profile, the treatment interruption rate was higher in the IO-TKI group than in the IO-IO group (70.3% vs. 49.2%; p = 0.005). In contrast, the IO-IO group had a higher corticosteroid administration rate (43.3% vs. 20.3%; p = 0.001). CONCLUSION: IO-TKI therapy exhibited superior effectiveness over IO-IO therapy in terms of PFS improvement and immediate disease progression prevention and was associated with a higher risk of treatment interruption and a lower risk of needing corticosteroids.

Neutrophil-to-lymphocyte ratio is a prognostic factor reflecting immune condition of tumor microenvironment in squamous cell lung cancer.

Inflammatory factors in the peripheral blood, such as the C-reactive protein level and neutrophil-to-lymphocyte ratio (NLR), are prognostic markers in multiple types of cancer, including non-small cell lung cancer (NSCLC). However, the association between inflammatory factors and prognosis based on histological types has not been adequately reported. In addition, the relationship between these factors and the immune condition of the tumor microenvironment (TME) is unclear. In this single center, retrospective study, we first investigated the relationship between preoperative inflammatory markers and clinical outcomes in 176 patients with NSCLC who underwent surgery. Lung adenocarcinoma (LUAD) showed no significant prognostic marker, whereas for lung squamous cell carcinoma (LUSC), a multivariate analysis showed that a high NLR was significantly associated with postoperative recurrence. In LUSC patients, the median time of postoperative recurrence-free survival in patients with a low NLR was longer than that in patients with a high NLR. We then compared the tumor-infiltrating lymphocyte (TIL) profile with inflammatory markers in peripheral blood and found that the NLR was negatively correlated with the frequencies of T cells and B cells in LUSC tissues. Thus, the NLR is a useful predictive biomarker for postoperative recurrence and may reflect the immune condition of the TME in LUSC.

Comparisons of survival and surgical outcomes between minimally invasive partial nephrectomy and radical nephrectomy in elderly patients with stage 1 renal cell carcinoma.

AIM: We compared survival and perioperative outcomes of robot-assisted laparoscopic partial nephrectomy (RAPN) and laparoscopic radical nephrectomy (LRN) for older patients (age 70 years or older) with stage 1 renal cell carcinoma (RCC). METHODS: This retrospective, single-center study included 260 patients who underwent RAPN and 44 patients who underwent LRN. The overall survival (OS) and perioperative outcomes were compared between these two groups using an inverse probability of treatment weighting (IPTW) analysis. RESULTS: Compared with the LRN group, a trend of more complications was observed in the RAPN group, including a higher body mass index (24 vs. 22 kg/m2 ; P = 0.0002) and higher rates of hypertension (77% vs. 55%; P = 0.0029) and chronic kidney disease (62% vs. 36%; P = 0.0027). After adjustment by the IPTW analysis, the RAPN group had a shorter operative time (143 vs. 282 min; P = 0.033), shorter postoperative length of hospital stay (PLOS) (4.1 vs. 7.9 days; P = 0.004), and less change in the estimated glomerular filtration rate during surgery (-8.4% vs. -32%; P < 0.0001) than the LRN group; however, the perioperative complication rates were similar. Patients who underwent RAPN had better 5-year OS than those who underwent LRN (95% vs. 90%; log-rank, P = 0.017). CONCLUSION: RAPN resulted in better OS and surgical outcomes, with shorter operative time, shorter PLOS, and better renal function preservation, than LRN for older patients with stage 1 RCC. Therefore, RAPN may be the primary option for patients indicated for surgical intervention. Geriatr Gerontol Int 2024; 24: 269-274.

Association Between Kidney Function and Outcomes Following Immune Checkpoint Inhibitor-Based Combination Therapy in Patients With Advanced Renal Cell Carcinoma.

BACKGROUND: It remains unclear whether kidney function affects outcomes following immune checkpoint inhibitor (ICI)-based combination therapy for advanced renal cell carcinoma (RCC). METHODS: We retrospectively evaluated data of 167 patients with advanced RCC, including 98 who received ICI dual combination therapy (ie, immunotherapy [IO]-IO) and 69 who received ICI combined with tyrosine kinase inhibitor (TKI) (ie, IO-TKI). In each regimen, treatment profiles were assessed according to the grade of chronic kidney disease (CKD) as defined by the KDIGO 2012 criteria. RESULTS: Of the 98 patients who received IO-IO, 31 (32%), 30 (31%), 15 (15%), and 22 (22%) had CKD G1/2, G3a, G3b, and G4/5, respectively. Of the 69 patients who received IO-TKI, 18 (26%), 25 (36%), and 26 (38%) had G1/2, G3a, and G3b/4/5, respectively. Regarding efficacy, progression-free survival, overall survival, or objective response rate was not different according to the CKD grade in both treatment groups (P > .05). Regarding safety, the rate of adverse events, treatment interruption, or corticosteroid administration was not different according to the CKD grade in the IO-IO group (P > .05), whereas in the IO-TKI group, the incidence of grade ≥ 3 adverse events were significantly higher (P = .0292), and the rates of ICI interruption (P = .0353) and corticosteroid administration (P = .0685) increased, according to the CKD grade. CONCLUSION: There is a differential safety but comparable efficacy profile between the IO-IO and IO-TKI regimens in patients with CKD. Further prospective studies are required to confirm these findings.

Real-world outcomes of nivolumab plus ipilimumab combination therapy for advanced renal cell carcinoma in Japanese patients: data with a minimum of 3 years of follow-up.

BACKGROUND: Long-term follow-up data regarding treatment outcomes of nivolumab plus ipilimumab combination therapy for advanced renal cell carcinoma as a first-line therapy are limited in real-world Japanese populations. METHODS: We retrospectively evaluated data of 56 advanced renal cell carcinoma patients treated with nivolumab plus ipilimumab, with a follow-up of at least 3 years. Survival, tumour response and adverse event profiles were assessed. RESULTS: A total of 41 patients (73%) were histopathologically diagnosed with clear-cell renal cell carcinoma, and 34 (61%) were categorized into the International Metastatic renal cell carcinoma Database Consortium intermediate-risk group. The median follow-up period was 34.4 months. Regarding an effectiveness profile, median progression-free survival, time to treatment failure and overall survival were 9.01, 12.5 and 49.0 months, respectively. Objective response was observed in 27 patients (48%), including eight patients with complete response (14%), and the median duration of response was 30.8 months. Multivariate analyses showed that clear-cell histology was an independent factor of longer overall survival (hazard ratio: 0.23, P = 0.0013). Regarding safety profiles, adverse events of any grade and those with grade ≥3 developed in 40 (71%) and 25 patients (45%), respectively. Median time to adverse event development was 1.68 months. Treatment was interrupted in 28 patients (50%), and corticosteroid administration was needed in 25 (45%). CONCLUSION: The 3-year follow-up data showed that nivolumab plus ipilimumab combination therapy exhibited a feasible effectiveness in real-world Japanese patients with advanced renal cell carcinoma. Accordingly, the high risk of adverse event development, which often requires treatment withdrawal and corticosteroid administration, should be considered.

Renal cell carcinoma outcomes in end-stage renal disease: A 40-year study from two Japanese institutions.

OBJECTIVES: The objective of the study was to analyze the outcomes of patients with renal cell carcinoma (RCC) arising in end-stage renal disease (ESRD) over a 40-year span. METHODS: We retrospectively evaluated data of patients with ESRD-RCC diagnosed between 1979 and 2020 at two institutions. We assessed changes in stage, surgical approaches, and cancer-specific survival (CSS) following nephrectomy according to era between ESRD-RCC and sporadic RCC. Furthermore, perioperative outcomes in patients with ESRD-RCC were compared between laparoscopic and open surgery. RESULTS: Patients with ESRD-RCC (n = 549) were diagnosed at an earlier stage (p = 0.0276), and the ratio of laparoscopic nephrectomy was increased (p < 0.0001) according to eras. Since 2000 (i.e., after implementation of laparoscopic nephrectomy), patients with ESRD-RCC (n = 305) had significantly shorter CSS (p = 0.0063) after nephrectomy than sporadic RCC (n = 2732). After adjustment by multivariate analysis and propensity score matching, ESRD status was independently associated with shorter CSS (p = 0.0055 and p = 0.0473, respectively). Improved CSS in sporadic RCC (p < 0.0001), but not ESRD-RCC (p = 0.904), according to era contributed to this difference. Laparoscopic nephrectomy showed favorable outcomes, including shorter surgery time, lower estimated bleeding volumes, transfusion rates, and readmission rates, and shorter postoperative hospitalization than open nephrectomy (p < 0.05). CONCLUSIONS: Advances in diagnostic and treatment modalities potentially enable early diagnosis and minimally invasive surgery for patients with ESRD-RCC. As ESRD-RCC may not present indolently, careful post-operative monitoring is needed.

Predictive factors and oncological outcomes of pathological T3a upstaging in patients with clinical T1 renal cell carcinoma undergoing partial nephrectomy.

OBJECTIVES: To investigate predictive factors and oncological outcomes of pathological T3a upstaging in renal cell carcinoma patients who were initially diagnosed as clinical T1 and treated with partial nephrectomy. METHODS AND MATERIALS: The clinical records and survival data of 1617 patients, who had undergone partial nephrectomy for clinical T1 renal cell carcinoma at Tokyo Women's Medical University, Tokyo, Japan between January 2011 and December 2020, were analyzed retrospectively. RESULTS: Of 1617 clinical T1 renal cell carcinoma patients who underwent partial nephrectomy, 28 (1.73%) had pathological T3a upstaging. In the multivariable analysis for pathological T3a upstaging using logistic regression models, male sex and clinical T1b were significant factors associated with pathological T3a upstaging (male sex: odds ratio = 5.07, 95% confidence interval: 1.18-21.8, clinical T1b: odds ratio = 8.36, 95% confidence interval: 3.56-19.6). The Kaplan-Meier method of the recurrence-free survival showed shorter recurrence-free survival in patients with pathological T3a upstaging than in those with pathological T1 (P < 0.0001). In the multivariable analysis using Cox proportional hazards regression models, pathological T3a upstaging was no longer significantly associated with recurrence-free survival after adjustment for other pathological factors (hazard ratio = 1.59, 95% confidence interval: 0.58-4.36). In a sensitivity analysis that analyzed its components individually instead of whole pathological T3a, neither perinephric fat invasion, sinus fat invasion, nor renal vein invasion was associated with recurrence-free survival. CONCLUSIONS: Male sex and clinical T1b were significant predictors for pathological T3a upstaging after partial nephrectomy in clinical T1 renal cell carcinoma patients. Although patients with pathological T3a upstaging had worse recurrence-free survival compared with those without upstaging, multivariable analyses revealed that pathological T3a upstaging was not an independent predictor for poor recurrence-free survival.

Surgical and functional outcomes of repeat robot-assisted laparoscopic partial nephrectomy compared with repeat open partial nephrectomy.

OBJECTIVES: To examine the surgical and functional outcomes of patients who have undergone repeat open partial nephrectomy (reOPN) or robot-assisted laparoscopic partial nephrectomy (reRAPN). METHODS: Until May 2022, 3310 patients with renal tumors underwent nephron-sparing surgery (NSS) at affiliated institutions. Of these, 22 and 17 patients who underwent reOPN and reRAPN, respectively, were included in this study. RESULTS: No significant differences were found between the groups in terms of sex, age, comorbidities, recurrent tumor size at repeat NSS, interval from recurrence to initial NSS, and nephrometry score. ReRAPN had a shorter operative time (median: 138.0 vs. 214.0 min; p = 0.0023) and less estimated blood loss (median: 50.0 vs. 255.0 mL; p = 0.0261) than reOPN. The incidence of complications with Clavien-Dindo grade ≥ 2 was higher in the reOPN group than in the reRAPN group (31.8 vs. 5.9%; p = 0.0467). The mean decrease in the estimated glomerular filtration rate at 3 months postoperatively was not significantly different between the groups. The trifecta achievement rates in the reRAPN (64.7%) and reOPN (27.3%) groups were significantly different (p = 0.0194). On multivariate analysis, age and surgical method were significant predictors of trifecta achievement after partial nephrectomy. CONCLUSIONS: There were no differences in postoperative renal functional outcomes between reOPN and reRAPN. ReRAPN is superior to reOPN in terms of surgical burden. Therefore, ReRAPN is an important minimally invasive surgery for recurrent renal cell carcinoma.

Real-world efficacy and safety of cabozantinib following immune checkpoint inhibitor failure in Japanese patients with advanced renal cell carcinoma.

BACKGROUND: Real-world data of cabozantinib after failure of immune checkpoint inhibitors for advanced renal cell carcinoma in Japanese population are limited. Additionally, prognostic factors of cabozantinib in this setting are still unknown. METHODS: We retrospectively evaluated data of 56 patients treated with cabozantinib subsequent to failed immune checkpoint inhibitors at four institutions. Regarding the efficacy profile, progression-free survival, overall survival and objective response rate were assessed. In terms of the safety profile, rate of adverse events, dose reduction and treatment interruption were assessed. Furthermore, risk factors of progression-free survival were analyzed. RESULTS: Twenty-nine patients (52%) were treated with cabozantinib as second-line therapy. Most frequent prior immune checkpoint inhibitor treatment was nivolumab plus ipilimumab combination therapy as first-line therapy (n = 30, 54%). Median progression-free survival and overall survival were 9.76 and 25.5 months, respectively, and objective response rate was 34%. All patients experienced at least one adverse event, and grade ≥ 3 adverse events were observed in 31 patients (55%). Forty-four (79%) and 31 (55%) patients needed dose reduction and treatment interruption, respectively. Multivariate analysis showed that reduced initial dose (i.e. <60 mg) (hazard ratio: 2.50, P = 0.0355) and presence of lymph node metastasis (hazard ratio: 2.50, P = 0.0172) were independent factors of shorter progression-free survival. CONCLUSION: Cabozantinib in Japanese patients with advanced renal cell carcinoma who failed immune checkpoint inhibitors was efficacious and had a manageable safety profile. These results appear to be similar to those of previous clinical trials.

Tumor-infiltrating Leukocyte Profiling Defines Three Immune Subtypes of NSCLC with Distinct Signaling Pathways and Genetic Alterations.

Resistance to immune checkpoint blockade remains challenging in patients with non-small cell lung cancer (NSCLC). Tumor-infiltrating leukocyte (TIL) quantity, composition, and activation status profoundly influence responsiveness to cancer immunotherapy. This study examined the immune landscape in the NSCLC tumor microenvironment by analyzing TIL profiles of 281 fresh resected NSCLC tissues. Unsupervised clustering based on numbers and percentages of 30 TIL types classified adenocarcinoma (LUAD) and squamous cell carcinoma (LUSQ) into the cold, myeloid cell-dominant, and CD8+ T cell-dominant subtypes. These were significantly correlated with patient prognosis; the myeloid cell subtype had worse outcomes than the others. Integrated genomic and transcriptomic analyses, including RNA sequencing, whole-exome sequencing, T-cell receptor repertoire, and metabolomics of tumor tissue, revealed that immune reaction-related signaling pathways were inactivated, while the glycolysis and K-ras signaling pathways activated in LUAD and LUSQ myeloid cell subtypes. Cases with ALK and ROS1 fusion genes were enriched in the LUAD myeloid subtype, and the frequency of TERT copy-number variations was higher in LUSQ myeloid subtype than in the others. These classifications of NSCLC based on TIL status may be useful for developing personalized immune therapies for NSCLC. Significance: The precise TIL profiling classified NSCLC into novel three immune subtypes that correlates with patient outcome, identifying subtype-specific molecular pathways and genomic alterations that should play important roles in constructing subtype-specific immune tumor microenvironments. These classifications of NSCLC based on TIL status are useful for developing personalized immune therapies for NSCLC.

Association between lung immune prognostic index and survival of patients with metastatic urothelial carcinoma treated with pembrolizumab.

INTRODUCTION AND OBJECTIVE: Lung immune prognostic index score (LIPI), calculated using the derived neutrophil-lymphocyte ratio and lactate dehydrogenase level, is reported for use in numerous malignancies, while its role on metastatic urothelial carcinoma (mUC) treated with pembrolizumab remains limited. We aimed to investigate association between LIPI and outcomes in this setting. METHODS: We retrospectively evaluated 90 patients with mUC treated with pembrolizumab at four institutions. The associations between three LIPI groups and progression-free survival (PFS), overall survival (OS), objective response rates (ORRs) or disease control rates (DCRs) were assessed. RESULTS: Based on the LIPI, good, intermediate, and poor groups were observed in 41 (45.6%), 33 (36.7%), and 16 (17.8%) patients, respectively. The PFS and OS were significantly correlated with the LIPI (median PFS: 21.2 vs. 7.0 vs. 4.0 months, p = 0.001; OS: 44.3 vs. 15.0 vs. 4.2 months, p < 0.001 in the LIPI good vs. intermediate vs. poor groups). Multivariable analysis further revealed that LIPI good (vs. intermediate or poor, hazard ratio: 0.44, p = 0.004) and performance status = 0 (p = 0.015) were independent predictors of a longer PFS. In addition, LIPI good (hazard ratio: 0.29, p < 0.001) were shown to be associated with a longer OS together with performance status = 0 (p < 0.001). The ORRs tended to be different among patients with Good LIPI compared with Poor, and DCRs were significantly different among the three groups. CONCLUSIONS: LIPI, a simple and convenient score, could be a significant prognostic biomarker of OS, PFS, and DCRs for mUC treated with pembrolizumab.

Long-time Survival of a Renal Transplant Recipient With Metastatic Mucinous Tubular and Spindle Cell Carcinoma: A Case Report.

BACKGROUND/AIM: Mucinous tubular and spindle cell carcinoma (MTSCC) of the kidney is a rare histological type of renal cell carcinoma (RCC). There are few reports of MTSCC occurring in renal transplant recipients (RTRs). The aim of this study was to report a case of long-term survival of a RTR with metastatic MTSCC of the kidney with sarcomatoid changes. CASE REPORT: A 53-year-old male with a left retroperitoneal tumor was referred to our department. He had been receiving hemodialysis since 1991 and underwent kidney transplantation in 2015. Computed tomography (CT) revealed suspected RCC, and a radical nephrectomy was performed in June 2020. Pathological findings revealed MTSCC with sarcomatoid changes. After the surgery, multiple metastases appeared in the bilateral adrenals, skin, para-aortic lymph nodes, muscles, mesocolon, and liver. We treated the patient with metastasectomy, radiation therapy, and sequential systemic therapy with tyrosine kinase inhibitors (TKI). Two years after the initial surgery, the patient died of cancer while controlling its progression. CONCLUSION: We report a RTR with aggressive and metastatic MTSCC with sarcomatoid changes, resulting in a longer survival time relative to multimodal therapy.